10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2022

Commission File Number: 001-39979

VOR BIOPHARMA INC.

(Exact name of registrant as specified in its charter)

100 Cambridgepark Drive, Suite 101Cambridge, Massachusetts 02140

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (617) 655-6580

Securities registered pursuant to Section 12(b) of the Act:

Title of each class TradingSymbol(s) Name of each exchange on which registered

Common Stock, $0.0001 par value per share VOR Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No ☒

Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

As of June 30, 2022, the last day of the registrant’s most recently completed second fiscal quarter, the aggregate market value of the registrant's common stock, $0.0001 par value per share (“Common Stock”), held by non-affiliates of the registrant was approximately $115,730,496 based upon the closing price of the Common Stock on June 30, 2022.

The number of shares of registrant’s Common Stock outstanding as of March 17, 2023 was 66,373,784.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s Proxy Statement for its 2023 Annual Meeting of Stockholders, to be filed with the Securities and Exchange Commission no later than 120 days after December 31, 2022, are incorporated by reference in Part III of this Annual Report on Form 10-K.

Table of Contents

Page

PART I

Item 1. Business 5

Item 1A. Risk Factors 50

Item 1B. Unresolved Staff Comments 112

Item 2. Properties 112

Item 3. Legal Proceedings 112

Item 4. Mine Safety Disclosures 112

PART II

Item 6. [Reserved] 113

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 125

Item 8. Financial Statements and Supplementary Data 125

Item 9A. Controls and Procedures 125

Item 9B. Other Information 126

Item 9C Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 126

Part III

Item 10. Directors, Executive Officers and Corporate Governance 127

Item 11. Executive Compensation 127

Item 14 Principal Accountant Fees and Services 127

PART IV

Item 15. Exhibits and Financial Statement Schedules 128

Note Regarding Company References

Throughout this Annual Report on Form 10-K (“Annual Report”), the “Company,” “Vor,” "Vor Bio," “Vor Biopharma Inc.,” “we,” “us,” and “our,” except where the context requires otherwise, refer to Vor Biopharma Inc. and its consolidated subsidiary, and “our board of directors” refers to the board of directors of Vor Biopharma Inc.

Special Note Regarding Forward-Looking Statements and Industry Data

This Annual Report contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this Annual Report, including statements regarding our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, and objectives of management, are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “would,” “expect,” “plan,” “anticipate,” “could,” “might,” “intend,” “target,” “ongoing,” “project,” “estimate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions intended to identify statements about the future. These statements speak only as of the date of this Annual Report and involve known and unknown risks, uncertainties and other important factors that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by the forward-looking statements. We have based these forward-looking statements largely on our current expectations and projections about future events and financial trends that we believe may affect our business, financial condition and results of operations. These forward-looking statements include, without limitation, statements about:

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the timing, progress and results of our preclinical studies and clinical trials of our product candidates, including statements regarding the timing and pace of initiation, enrollment and completion of studies or trials and related preparatory work, the period during which the results of the trials will become available and plans with respect to our research and development programs;

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the timing and success of our in-house or third party clinical manufacturing capabilities and efforts;

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the timing of any submission of filings for regulatory approval of, and our ability to obtain and maintain regulatory approvals for, our product candidates for any indication;

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our ability to identify patients with the diseases treated by our product candidates, and to enroll patients in trials;

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our expectations regarding the market acceptance and opportunity for and clinical utility of our product candidates, if approved for commercial use;

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our expectations regarding the scope of any approved indication for any product candidate;

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our ability to successfully commercialize our product candidates;

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our estimates of our expenses, ongoing losses, future revenue, capital requirements and our need for or ability to obtain additional funding;

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our ability to establish or maintain collaborations or strategic relationships;

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our ability to identify, recruit and retain key personnel, including executive officers and members of management;

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our reliance upon intellectual property licensed from third parties and our ability to obtain such licenses on commercially reasonable terms or at all;

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our ability to protect and enforce our intellectual property position for our product candidates, and the scope of such protection;

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our financial performance;

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the period over which we estimate our existing cash, cash equivalents and marketable securities will be sufficient to fund our future operating expenses and capital expenditure requirements;

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our competitive position and the development of and projections relating to our competitors or our industry;

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the impact of laws and regulations; and

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our expectations regarding the time during which we will be an emerging growth company under the Jumpstart Our Business Startups Act of 2012.

You should read this Annual Report and the documents that we have filed as exhibits to this Annual Report completely and with the understanding that our actual future results may be materially different from what we expect. The forward-looking statements contained in this Annual Report are made as of the date of this Annual Report, and we do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law. We have included important factors in this Annual Report, particularly in the “Summary Risk Factors” and “Risk Factors” sections, that could cause actual results or events to differ materially from the forward-looking statements that we make.

This Annual Report includes statistical and other industry and market data, which we obtained from our own internal estimates and research, as well as from industry and general publications and research, surveys, and studies conducted by third parties. Industry publications, studies, and surveys generally state that they have been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. While we believe that each of these studies and publications is reliable, we have not independently verified market and industry data from third-party sources. While we believe our internal company research is reliable and the market definitions are appropriate, neither such research nor these definitions have been verified by any independent source.

Summary Risk Factors

Our business is subject to a number of risks that if realized could materially affect our business, financial condition, results of operations, cash flows and access to liquidity. These risks are discussed more fully in the “Risk Factors” section of this Annual Report. Our principal risks include the following:

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We have incurred significant net losses since inception. We expect to incur net losses for the foreseeable future and may never achieve or maintain profitability.

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We will need substantial additional funding. If we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate our research and product development programs or future commercialization efforts.

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We have a limited operating history, have not yet completed any clinical trials and have no history of commercializing products, which may make it difficult to evaluate the success of our business to date and to assess our future viability.

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Engineered hematopoietic stem cells (“eHSCs”) are a novel technology that is not yet clinically validated for human use. The approaches we are taking to create eHSCs are unproven and may never lead to marketable products.

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We are substantially dependent on the success of our two most advanced product candidates, trem-cel and VCAR33ALLO. If we are unable to complete development of, obtain approval for and commercialize trem-cel or VCAR33ALLO in a timely manner, our business will be harmed.

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We may not be successful in our efforts to identify, develop or commercialize additional product candidates. If these efforts are unsuccessful, we may never become a commercial stage company or generate any revenues.

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We have not successfully tested our product candidates in clinical trials and any favorable preclinical results are not predictive of results that may be observed in clinical trials.

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Development of a product candidate such as trem-cel, which is intended for use in combination or in sequence with an already approved therapy, will present increased complexity and more or different challenges than development of a product candidate for use as a single agent.

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If our product candidates, the delivery modes we rely on to administer them, and/or the conditioning, administration process or related procedures or treatments which may be used alongside our product candidates cause serious adverse events, undesirable side effects or unexpected characteristics, such events, side effects or characteristics could delay or prevent regulatory approval of the product candidates, limit their commercial potential or result in significant negative consequences following any potential marketing approval, even if these side effects or characteristics are unrelated to our product candidate.

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We face significant competition in an environment of rapid technological change, and there is a possibility that our competitors may achieve regulatory approval before us or develop therapies that are safer or more advanced or effective than ours, which may harm our financial condition and our ability to successfully market or commercialize our product candidates, if approved.

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Adverse public perception of genetic medicines, and of genome engineering in particular, including as a result of other trials out of our control, such as the VCAR33AUTO trial currently sponsored by the National Marrow Donor Program, may negatively impact regulatory approval of, and/or demand for, our potential products.

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Success in preclinical studies or clinical trials may not be indicative of results in future clinical trials, particularly for our clinical trials that involve only a small number of patients.

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Genome engineering technology is subject to a number of challenges and risks. Because genome engineering technology is novel and the regulatory landscape that will govern our product candidates is uncertain and may change, we cannot predict the time and cost of obtaining regulatory approval, if we receive it at all, for our product candidates.

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Because we are developing product candidates using new technologies, as well as potential mechanisms of action for which there are few precedents, there is increased risk that the U.S. Food and Drug Administration, the European Medicines Agency or other regulatory authorities may not consider the endpoints of our clinical trials to provide clinically meaningful results and that these results may be difficult to analyze.

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Interim “top-line” and preliminary results from our clinical trials that we may announce or publish from time to time may change as more patient data become available and are subject to audit and verification procedures that could result in material changes in the final data. Investors and analysts may have difficulty analyzing our interim and preliminary results or may not consider them to be meaningful.

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If we experience significant delays or difficulties in the enrollment of patients in clinical trials, including with respect to completing a complex donor identification and screening process, the cost of developing product candidates could increase and our receipt of necessary regulatory approvals could be delayed or prevented.

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If we are unable to successfully identify patients who are likely to benefit from our product candidates or eligible donors, or experience significant delays in doing so, we may not realize the full commercial potential of our product candidates.

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We have initiated manufacturing at our in-house facility, but until and unless we complete the total transfer of our manufacturing capabilities in-house, we will continue to contract with third parties for the manufacture and supply of materials for development of our product candidates and advancement of our current clinical trial, as well as our research programs and preclinical studies, and we expect to continue to do so for future clinical trials and for commercialization of our product candidates. This reliance on third parties increases the risk that we will not have sufficient quantities of such materials, product candidates or any products that we may develop and commercialize, or that such supply will not be available to us at an acceptable cost, which could delay, prevent or impair our development or commercialization efforts.

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We are highly dependent on intellectual property licensed from third parties and termination of any of these licenses could result in the loss of significant rights, which would harm our business.

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We may not be successful in acquiring or in-licensing necessary rights to key technologies underlying our product candidates.

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Third-party claims of intellectual property infringement, misappropriation or other violations may prevent or delay our product discovery and development efforts and have a material adverse effect on our business.

PART I

Item 1. Business.

Overview

Vor Bio is a clinical-stage company with a vision to cure blood cancers through cell and genome engineering. Our mission is to change the standard of care for patients with blood cancer by engineering hematopoietic stem cells (“HSCs”) to enable the use of targeted therapies post-transplant.

Our initial focus is on patients suffering from acute myeloid leukemia (“AML”). For many of these patients, hematopoietic stem cell transplant (“HSCT”) is the standard of care treatment and the only way to achieve durable remission or a cure. Despite undergoing HSCT, approximately 40% of patients experience a relapse of their cancer and subsequently face an extremely poor prognosis, with two-year survival rates of less than 20%.

The traditional tumor targeting approach to treating blood cancers such as AML focuses on cancer cells expressing a target antigen. However, very few targets are tumor-specific, as healthy cells usually express these same target antigens alongside cancer cells. While technologies may improve the specificity of target antigen binding or enhance potency, these approaches are subject to the same fundamental biological limitation of killing healthy cells expressing these targets, known as on-target toxicity. A number of targeted therapies have failed in clinical development, and those that have succeeded possess limited utility and narrow applicability, in part due to their on-target toxicity.

Vor Bio’s proprietary platform aims to change the traditional target tumor approach by genetically engineering healthy cells by removing therapeutic targets, thereby enabling the use of targeted therapies post-transplant.

Changing the Thinking on Tumor Targeting

Leveraging our expertise in HSC biology and genome engineering, we genetically modify HSCs to remove surface targets and then provide these cells as hematopoietic stem cell transplants to patients. Once these cells engraft into bone marrow, the patient’s healthy cells should be protected because they no longer express the surface target, leaving only the cancerous cells exposed. We believe this will unlock the potential of targeted therapies to

selectively destroy cancerous cells while sparing healthy cells. As a result, our engineered HSCs (“eHSCs”) are designed to limit the on-target toxicities associated with these targeted therapies, thereby enhancing their utility, and broadening their applicability.

A Novel Treatment Approach for Blood Cancers

We are developing our lead eHSC product candidate, tremtelectogene empogeditemcel (trem-cel), formerly VOR33, which we believe has the potential to transform the treatment for AML and other blood cancers. CD33 is a clinically validated target for AML, and we use genome engineering technology to remove CD33 surface targets from HSCs to create trem-cel. Data from preclinical studies from multiple independent laboratories, alongside data from human genetics databases, show that CD33 can be removed from HSCs without any deleterious impact on cell biology.

We have initiated VBP101, a Phase 1/2a clinical trial in patients with CD33-positive AML who are at high risk of relapse. The primary goals of the trial are to evaluate tolerability and feasibility of the trem-cel stem cell transplant, with a focus on confirming that trem-cel can engraft normally. Following engraftment, patients are eligible to be treated with Mylotarg®, a CD33-directed antibody drug conjugate (“ADC”) therapy, in order to potentially prolong leukemia-free survival and provide evidence that trem-cel protects against the myelosuppression that typically accompanies treatment with Mylotarg. Initial clinical data from one patient from VBP101 showed trem-cel exhibited robust engraftment five months post-transplant through multiple cycles of Mylotarg, at the initial dose level.

Our proprietary eHSC technology is designed to confer advantages and address several limitations associated with existing cell therapy processes. Our manufacturing of eHSCs is a fast and elegant process that leads to a rapid vein-to-vein time which we believe can easily integrate into existing standard of care. Additionally, preclinical studies of trem-cel demonstrated a high degree of genome engineering precision with highly reproducible results across multiple independent healthy donors, which we have now replicated across large-scale clinical batches.

We intend to pair future eHSC product candidates with targeted therapeutics such as our VCAR33 programs, chimeric antigen receptor (“CAR”)-T therapies designed to target CD33, as well as with potentially best-in-class targeted therapies from collaborators, to bring potentially transformative outcomes to patients and establish new standard of care Treatment Systems for blood cancers.

We believe that the combination of trem-cel followed by treatment with VCAR33ALLO, our in-house CD33-directed CAR-T program, which we refer to as the trem-cel + VCAR33 Treatment System, in the post-transplant setting has the potential to transform patient outcomes and may offer the potential for cures for patients that have limited treatment options. The Treatment System would utilize the same healthy donor allogenic cell source for both trem-cel and VCAR33ALLO. We plan to collect initial data on trem-cel from the VBP101 clinical trial and initial clinical data from the first-in-human trial studying the VCAR33ALLO program prior to the Investigational New Drug (“IND”) submission for the Treatment System. We believe this approach may allow for a methodical development pathway for this novel-novel treatment combination.

We are also pursuing our first multi-targeted CD33-CLL1 Treatment System comprising a CD33-CLL1 multiplex-edited eHSC therapy and a CD33-CLL1 multi-specific CAR-T therapy. These next-generation, multiplex-edited eHSCs may enable a wide range of treatment options post-transplant, including the use of multi-specific CAR-T therapies.

We believe our proprietary technology has broad applicability beyond CD33, including targets such as CD123, EMR2, and CD5. Leveraging our platform, we are rapidly advancing the creation and preclinical testing of multiplex-engineered eHSCs, in which multiple surface targets are removed, potentially obviating concern around tumor heterogeneity and potential escape mechanisms.

Acute Myeloid Leukemia Overview

AML is the most common type of acute leukemia in adults and is characterized by excessive proliferation of myeloid stem cells and their failure to properly differentiate into mature blood cells. There are an estimated 42,500 new diagnoses of AML each year in the United States, Europe and Japan. The median five-year survival rate for patients with AML is less than 30%, but there are significant differences in prognosis depending on several factors, including the age of the patient at diagnosis.

Current first-line treatments for patients with AML typically involve aggressive combination chemotherapy regimens with the goal of inducing disease remission long enough to allow the patient to undergo a potentially curative HSCT. The recommended treatment for AML for patients younger than 60 years and for older patients who can tolerate intensive chemotherapy is a regimen referred to as 7+3, involving seven days of continuous dosing with the chemotherapy agent cytarabine along with short infusions of the chemotherapy agent daunorubicin on days one through three. These induction chemotherapy regimens are usually not curative, and without post-remission therapy such as HSCT, AML is likely to return within several months.

Following successful induction chemotherapy and prior to HSCT, patients undergo myeloablation, a procedure designed to eliminate more of the remaining tumor cells, but one that also leads to the destruction of the patient’s HSCs. These HSCs are then replaced using cells from a matched healthy donor, resulting in reconstitution of the patient’s hematopoietic system.

Over the past 20 years, there has been an increasing trend in HSCTs for AML patients with over 16,000 allogeneic HSCT procedures performed in the United States between 2013 and 2017. AML was the most common disease treated by allogeneic HSCT, representing over 35% of all allogeneic HSCT procedures performed during this time period.

Unfortunately, in approximately 40% of AML patients who undergo HSCT, some tumor cells persist, and the patient’s cancer relapses. As shown in the figure below, AML patients treated with HSCT who were identified prior to HSCT as high risk of relapse, given presence of Minimal Residual Disease (“MRD”) biomarkers or active disease in bone marrow samples, or had MRD had an even higher relapse rate of 67%, with the vast majority of these patients relapsing within one year. Patients who had MRD negative disease, meaning that the number of tumor cells had been reduced to a level of approximately 0.1% of cells in a bone marrow sample, had a much lower and slower risk of relapse.

Myeloid Cancer Unmet Need is Large and Increasing

Following HSCT, patients have very few treatment options and generally receive no treatment despite being high risk of relapse, since anti-cancer therapies will compromise the integrity of the new HSCT. This includes the use of targeted therapies such as Mylotarg, where on-target toxicity may compromise the new bone marrow cells. Unfortunately, due in part to stagnant innovation in HSCT and limited post-transplant treatment options, the post-transplant survival for AML patients is approximately 44%, based on AML outcomes in the National Cancer Database from 1998 to 2011. Approximately 10,000 patients in the United States die from AML each year.

Our Strategy

Our mission is to change the standard of care for patients with blood cancer by engineering HSCs to enable use of targeted therapies post-transplant. Our strategy to accomplish this mission is as follows:

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Demonstrate trem-cel engrafts in patients and behaves like a typical HSCT. While extensive in vitro and animal experiments have studied the biological dispensability of CD33, the VBP101 Phase 1/2a clinical trial is the first time humans have received a stem cell transplant with CD33 surface targets deleted from the HSCs. Initial clinical data from two patients showed robust engraftment of these cells, an important proof of concept for our platform. This initial data supports that CD33 may be biologically dispensable, and that same phenomenon may also occur with additional targets we are studying, including CD123, EMR2, and CD5.

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Demonstrate trem-cel and progeny cells are protected from Mylotarg. As a CD33-directed targeted therapeutic, Mylotarg almost universally causes bone marrow toxicity in the form of cytopenias, which are decreased counts of blood cells such as neutrophils and platelets, which occurs even at low doses. Patients enrolled in the VBP101 Phase 1/2a clinical trial receive Mylotarg following their trem-cel transplant per a 3+3 dose escalation schema in the protocol. Initial clinical data in the first patient treated with Mylotarg showed neutrophil and platelet cell counts were maintained following three sequential Mylotarg doses at 0.5 mg/m2. We believe use of even more effective targeted therapies post-transplant may allow for longer relapse-free survival and our vision is to ultimately cure blood cancers by combining our eHSCs with these targeted therapies.

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Advance in-house targeted therapies, including our wholly owned CAR-T therapy VCAR33 programs. Our VCAR33 programs are CAR-T therapy candidates designed to target CD33, a clinically validated target for AML. VCAR33 is made up of two programs with different cell sources.

VCAR33ALLO uses allogeneic healthy donor-derived cells. There has been an increasing appreciation for the value of cell phenotype in CAR-T approaches, and HLA-matched healthy donor cells are a potentially superior cell phenotype with improved persistence and in vivo

expansion capability. We plan to submit an IND for this program in the first half of 2023 to support a Phase 1/2 clinical trial for patients with relapsed/refractory AML.

VCAR33AUTO uses autologous cells from each patient and is being studied in an ongoing Phase 1/2 clinical trial sponsored by the National Marrow Donor Program (“NMDP”) in young adult and pediatric patients with relapsed/refractory AML in a bridge-to-transplant study.

Clinical data generated from the VCAR33AUTO andVCAR33ALLO programs may inform the

development of important new therapies for patients with relapsed/refractory AML. In addition,

these programs will collect important safety and efficacy data to inform the Treatment Systems

discussed below.

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Advance Treatment Systems comprising eHSCs and CAR-Ts, starting with the trem-cel + VCAR33 Treatment System. We intend to combine trem-cel and VCAR33ALLO as the trem-cel + VCAR33 Treatment System where patients would first receive a trem-cel HSCT, then subsequently VCAR33ALLO generated from the same healthy donor source as trem-cel. We believe that such a Treatment System could result in long-lived CAR-T cells in the patient without major hematologic toxicities and potentially enable prolonged remissions or cures in the post-transplant setting. We plan to develop the trem-cel + VCAR33 Treatment System by generating initial data on trem-cel from the VBP101 clinical trial, alongside initial clinical data from the VCAR33ALLO program, prior to IND submission.

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Leverage our proprietary Vor Bio platform to discover and validate targets for additional eHSCs and CAR-Ts.We have applied expertise in HSC biology and genome engineering to focus on targets beyond CD33, including CD123, EMR2, and CD5. Additional targets may allow us to go beyond AML to target other cancers, and also provide multiplexing opportunities that allow modification of more than one target simultaneously, potentially obviating concerns around tumor heterogeneity or tumor escape mechanisms, and potentially allowing even more post-transplant treatment opportunities including multi-specific CAR-Ts. The CD33-CLL1 Treatment System is the first of such programs consisting of a multiplex-edited eHSC and multi-specific CAR-T.

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Further establish and leverage our in-house cGMP cell therapy manufacturing.HSCs are unique cell types that require specialized genome engineering techniques as well as specific handling and manipulation processes. We have built considerable know-how manipulating genes of these cells and have also designed a highly efficient manufacturing and release process for trem-cel that fits into the standard HSC transplant process. In September 2022, we completed the build-out of our own in-house clinical manufacturing facility at our Cambridge, MA headquarters. The facility has been designed to support flexible clinical manufacturing for our eHSC and CAR-T product candidate pipeline and allow enhanced strategic control.

Our Approach—Engineering Hematopoietic Stem Cells to Enable Targeted Therapies Post-Transplant.

Our proprietary platform aims to change the traditional approach to tumor targeting by removing target expression from healthy cells, thereby engineering the patient’s cells to improve the tumor specificity of targeted therapies. We accomplish this by genetically modifying healthy donor HSCs to remove select cell surface targets. By removing these targets, we make these donor HSCs and their progeny treatment-resistant to targeted therapies and enable these treatments to selectively destroy cancerous cells while sparing healthy cells. As a result, our eHSCs are designed to limit the on-target toxicities associated with these targeted therapies, thereby enhancing their utility and broadening their applicability. We believe that combining our eHSCs and targeted therapies, such as CAR-Ts, bispecific antibodies, and ADCs, has the potential to transform the treatment of blood cancers, such as AML.

Our Proprietary Vor Bio Platform

We have built a technology platform to realize our vision that allows for selective cancer targeting with highly potent targeted therapies by leveraging our expertise and recent advances in stem cell biology and genome engineering. Our approach is in stark contrast to conventional approaches that have focused solely on developing the therapeutic and have faced clinical limitations due to toxicities. The key components of our proprietary Vor Bio platform are the following:

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Leveraging Stem Cell Biology and Manufacturing Expertise.We have built an extensive understanding of the biology of HSCs to enable our eHSCs to retain their cellular viability and functionality during manipulation. In addition, we have built process development expertise centered around HSCs, enabling us to process these cells quickly, precisely, reproducibly, and efficiently for patients. We are continuing to develop our in-house clinical GMP manufacturing capabilities and facilities to further allow us to leverage our expertise and maintain strategic control over the manufacturing process.

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Applying Genome Engineering to Hematopoietic Stem Cells.Recent developments in genome engineering allow permanent changes to DNA in cells and all their progeny. We have assembled a team with extensive experience in applying genome engineering technologies to HSCs, which display distinct DNA repair mechanisms compared to many other cell types. We possess expertise in a variety of genome engineering technologies including CRISPR-Cas9, CRISPR analog enzymes, and base editing, and we are capable of multiplex editing using a variety of techniques.

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Unlocking the Potential of Targeted Therapies.We believe our eHSCs are a potential solution to the lack of tumor-specific targets and enable selective cancer targeting. Our solution allows for treatment with potent agents, such as CAR-T therapies, whose utility and applicability have previously been limited, in part, by on-target toxicity. We are designing and developing targeted therapies that are optimized for use with our eHSCs in the post-HSCT setting.

Our goal is to replace the patient’s HSCs with next-generation, treatment-resistant eHSCs that unlock the potential of highly potent targeted therapies by leveraging our platform and expertise. Our platform is adaptive and has the potential to engineer cells, whether autologous or allogeneic, whether collected from mobilized peripheral blood stem cells, bone marrow or cord blood-derived stem cells, and with any human leukocyte antigen (“HLA”) matching strategy, such as complete, incomplete or haploidentical matches. We also believe that our eHSCs could be used with any specific conditioning regimen and believe our platform could be used with either myeloablative or reduced-intensity conditioning regimens.

Vor Bio’s Novel Technology Platform

Advantages of Our eHSC Technology and Manufacturing Process

Our eHSC technology is designed to confer advantages and address limitations associated with existing cell therapy processes.

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Speed—Rapid Manufacturing Cycle and Vein-to-Vein Time. In contrast to other patient-specific cell therapies, such as CAR-T therapies and gene-modified allogeneic cell therapies, our eHSCs manufacturing is a rapid and elegant process that fits into the standard HSC transplant process. The

primary reason we can produce eHSCs so quickly is the lack of a need for cell expansion. Our approach to creating eHSCs also does not involve the insertion of new genetic material, thereby avoiding complications related to the use of delivery modalities necessary for gene insertion, such as the viral vectors used in CAR-T therapies. The relatively simple and streamlined process of creating our eHSCs provides significant advantages in the required manufacturing infrastructure and we are continuing to develop in-house clinical current manufacturing capabilities to support our planned clinical trials. We believe the efficiency and low capital expenditure of our manufacturing process should translate into higher scalability, a lower cost of goods, and easy integration into routine transplant practice.

Vor Bio Streamlined Manufacturing Process

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Investment in our own internal manufacturing facility. In September 2022, we initiated operations at our new in-house clinical manufacturing facility in Cambridge, Massachusetts to support our development of potentially transformative eHSCs and CAR-T therapeutic candidates for patients with blood cancers. The facility will provide us with end-to-end oversight over drug product for our planned clinical trials. With this new facility, we expect our manufacturing teams will be seamlessly integrated within our wider organization, a crucial component of our strategy as we continue to enroll our clinical studies. The facility has been designed to support clinical manufacturing for our cell therapy programs, including both eHSCs and CAR-T therapeutic candidates, and to be cGMP compliant. By integrating our internal research, process development, analytical development, manufacturing, and quality control testing capabilities under one roof, we aim to achieve flexible manufacturing capacity and to reduce the time and cost required to manufacture complex cell therapy clinical candidates.

Our Pipeline

Our pipeline of eHSC and CAR-T programs is shown below:

AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm

*The VCAR33AUTO construct is being studied in a Phase 1/2 clinical trial sponsored by the NMDP, and timing of data release is dependent on the investigators conducting the trial.

Our Programs

Trem-cel for the Treatment of Blood Cancers

Overview

Trem-cel is our lead eHSC product candidate created by genetically modifying healthy donor HSCs in order to remove the CD33 surface target. We intend to develop trem-cel as an HSCT product candidate to replace the standard of care in transplant settings. Once the trem-cel cells have engrafted, we believe that patients can be treated with anti-CD33 therapies, such as Mylotarg or our CAR-T therapy product candidates, with limited on-target toxicity. We have initiated VBP101, a Phase 1/2a clinical trial in patients with CD33-positive AML who are at high risk of relapse.

VBP101 Clinical Trial

Our IND application for trem-cel in patients with AML was accepted by the U.S. Food and Drug Administration ("FDA") in January 2021, and we have initiated VBP101, our first-in-human Phase 1/2a trial of trem-cel in combination with Mylotarg.

Trem-cel has received Fast Track designation for the treatment of AML from the FDA, allowing for potential facilitated development and expedited review process, and Orphan drug designation (“ODD”), which is granted by the FDA to a drug or biologic intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the U.S. ODD granted therapies entitle companies to development incentives including tax credits for clinical testing, prescription drug user fee exemptions, and seven-year marketing exclusivity in the event of regulatory approval.

The clinical strategy for trem-cel is to initially evaluate engraftment and tolerability, then assess clinical activity in subsequent clinical trials.

The primary goals of the VBP101 trial are to evaluate tolerability and feasibility, with a focus on confirming that trem-cel can engraft in patients in a timely manner. Patients will then be eligible for subsequent treatment with Mylotarg. While this trial is not designed to evaluate the efficacy of the combination of trem-cel and Mylotarg, we may generate data on the incidence of the previously documented hematopoietic toxicities associated with Mylotarg. Any observed protection from such on-target toxicity in this Phase 1/2a trial would serve as an important proof of principle for our research and development platform.

The VBP101 clinical trial is enrolling CD33-positive AML patients who are at a high risk of relapse. We have started our screening process with patients who have achieved morphologic remission, which means they have no detectable AML blasts in peripheral blood. As part of routine clinical practice, genetic profiling is also used to identify those patients who have disease markers associated with a high risk of disease relapse, such as MRD status. After the primary disease in these patients is put into remission, we expect a substantial number of patients will have MRD or other disease markers showing high risk of relapse and therefore will be candidates for trem-cel.

To administer trem-cel, HSCs from matched healthy donors are isolated, engineered into trem-cel and then introduced into patients following myeloablative conditioning. We expect that engraftment of trem-cel will occur within 28 days of administration, which occurs in over 90% of standard HSCT procedures. As a safety measure, we freeze and preserve a portion of the original donor cells to use in case of the failure of trem-cel to engraft. At day 60, we re-evaluate patients for disease status. Those patients with successful trem-cel grafts who experience relapse of their AML will then become eligible to be treated with therapeutic doses of Mylotarg. Other patients are treated with maintenance doses of Mylotarg once a month for four months to address any remaining MRD.

We expect the key analytical and clinical read-outs of the VBP101 clinical trial to include the following:

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Engraftment.Hematologic cell counts will be assessed following transplant with the expectation that absolute neutrophil cell counts will be greater than or equal to 500/mm3 by day 28 post-transplant for three consecutive days.

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Mylotarg Toxicities.Patients receiving Mylotarg usually exhibit significant myelosuppression within one to two weeks following dosing. Patients will be monitored for neutrophil and platelet cell counts following Mylotarg dosing, and will be assessed for suitability for receiving repeat Mylotarg dosing.

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Clinical Activity Observations.Following Mylotarg treatment, patients will be monitored for the presence of MRD, which are biomarkers in bone marrow indicating remaining presence of cancer. MRD positivity is a strong predictor of AML relapse, and change from MRD positive to negative status would be clinically meaningful. In addition, patients will be assessed for the incidence of relapse-free survival and overall survival.

Initial Clinical Data from the VBP101 Clinical Trial

In December 2022, we reported initial clinical data on the first patient (Patient 1) treated in the VBP101 trial; the patient was successfully transplanted with trem-cel and tolerated Mylotarg.

A product dose of 7.6 x106 CD34+ viable cells/kg, with a CD33 editing efficiency of 88% was manufactured. Following myeloablative conditioning, trem-cel was infused with no infusion reactions. The patient achieved neutrophil engraftment 10 days post-transplant which was within expectations for CD34-enriched transplants. Platelet recovery was observed on Day 22. Hematopoietic cell sub-population reconstitution was robust with over 90% of peripheral blood cells negative for CD33 expression, and 100% donor chimerism was achieved. These data provide proof-of-concept that trem-cel can engraft as expected and that CD33 does not appear to be biologically necessary for engraftment and hematopoietic reconstitution.

As of the last clinical data cut on February 6, 2023, (data presented at the 2023 TANDEM Meetings), neutrophil and platelet cell counts were maintained in Patient 1 approximately five months (147 days) after transplantation with trem-cel and following three sequential Mylotarg doses at 0.5 mg/m2. This suggests potential protection from Mylotarg-related hematotoxicity. The only adverse event observed possibly related to Mylotarg through dose 3 was low grade nausea and vomiting, a known side-effect of Mylotarg. Mylotarg first-dose pharmacokinetics revealed 0.5 mg/m2 achieved Cmax and AUC parameters equivalent to 1-2 mg/m2 and 4-5 mg/m2 accordingly, potentially due to the decreased CD33 antigen sink. Due to detectable MRD, Patient 1 was moved to other therapies following administration of the third dose of Mylotarg, subsequently relapsed, and remains on study for long-term follow-up.

In Patient 1, CD33-negative donor hematopoiesis was enriched across hematopoietic cell types following Mylotarg administration. In addition, the CD33 deletion was observed in donor cells of myeloid and lymphoid origin which were both enriched following Mylotarg, suggesting that CD33 is expressed in early hematopoietic cells and that Mylotarg treatment enriches for edited donor cells.

Patient 1 maintained neutrophil and platelet counts approximately five months (147 days) after transplantation with trem-cel. Due to detectable MRD, Patient 1 was moved to other therapies following administration of the third dose of Mylotarg, subsequently relapsed, and remains on study for long-term follow-up. Consistent with results from Patient 1, Patient 2 successfully received a trem-cel transplant and showed robust cell recovery with neutrophil engraftment occurring at Day 11 and platelet recovery on Day 17. Trem-cel was well tolerated, with no related and no unexpected adverse events (AEs) reported. Trem-cel was manufactured with 87% CD33 gene editing efficiency and the patient’s trem-cel dose was 3.2 x 106 CD34+ cells/kg.

Interest in enrollment in VBP101 continues to be strong with a high level of investigator enthusiasm at all nine study sites. We are moving forward with dose escalation of Mylotarg per the 3+3 dose escalation schema in the protocol and expect to report additional data by year-end 2023.

CD33 Targeted Therapies

A number of biologics investigated by third parties as potential therapeutics in AML and other hematopoietic malignancies have been based on targeting CD33, which, as shown in the figures below, is expressed, on average, in between approximately 85 to 90% of bulk AML patient samples and over 75% of leukemic stem cells.

Rate of expression in bulk AML patient samples and leukemic stem cells

CD33 is an attractive target for the development of AML therapeutics based on preclinical and clinical results from third parties demonstrating the ability of anti-CD33 directed therapies to deplete tumor cells. However, CD33-directed therapeutic approaches have had limited impact in improving the prognosis of patients with AML due in part to on-target toxicity. This on-target toxicity can have myelosuppressive effects, such as neutropenia, which is an abnormally low number of certain white blood cells, and thrombocytopenia, which is an abnormally low number of platelets. A summary of the historic experience following a single dose of Mylotarg is shown below.

The only CD33 targeted therapy approved by the FDA for the treatment of AML is gemtuzumab ozogamicin (“GO”), which is marketed by Pfizer under the brand name Mylotarg. Mylotarg is an ADC that targets CD33 on AML cells and is designed to deliver a potent cytotoxin directly to tumor cells. However, due to the expression of CD33 on a broad set of hematologic progenitor cells, Mylotarg not only attacks AML cells, but it also depletes healthy blood cells, including HSCs and other progenitor cells that express CD33. Primarily due to its toxicity profile, Mylotarg is currently used only in a limited setting, in both first line and relapsed/refractory disease. Without a solution to the problem of CD33 on-target toxicity, we expect all CD33-targeted therapies to produce thrombocytopenia and neutropenia which may result in the same limited clinical utility as Mylotarg.

We believe engineering the patient to remove CD33 is a unique approach designed to protect from on-target toxicity and unlock the potential of CD33 as a therapeutic target. By removing CD33 expression in healthy cells, we expect to render these cells and their progeny treatment resistant to CD33-directed therapies, thereby providing robust protection from these therapies’ cytotoxic effects.

Trem-cel Preclinical Data

Preclinical Proof of Concept

In preclinical studies, we observed the resistance of our eHSCs to Mylotarg. As shown in the figure below, we used in vitro cytotoxicity assays to measure the effects of various concentrations of Mylotarg on HSCs and their progeny (collectively, “HSPCs”) that have differentiated into myeloid lineage cells. We tested both wild type cells whose CD33 surface targets had not been manipulated (“CD33WT”) and cells that we had genetically engineered to remove CD33 (“CD33Del”). We observed that CD33Del cells had an approximately 70-fold increase in IC50 in comparison to CD33WT cells and, as expected, observed few differences in cell killing at extreme Mylotarg concentrations.

Mylotarg Cytotoxicity on CD33WT and CD33Del HSPCs

This was consistent with results from in vivo studies in which human HSPCs were engrafted for 16 weeks into 15 immune-compromised mice, with 15 mice used as a vehicle treated (“Vh”) control group. We investigated the impact of Mylotarg on CD14+ monocytes derived from these human HSPCs since CD14+ monocytes naturally express CD33 on their surface. As shown in the figure below, we observed that in the vehicle-treated groups, there was significant loss of CD14+ cells, while that population of cells was largely intact in the CD33Del arm, leading to a 61-fold higher CD14+ cell frequency in the CD33Del arm compared to the mock electroporated arm. These studies provide evidence of the resistance of CD33Del eHSCs and progeny to anti-CD33 therapies.

CD33WT and CD33Del HSC survival after exposure to Mylotarg

Removal of CD33—No Observed Impact on Biology

Data from preclinical studies from multiple independent laboratories, alongside data from human genetics databases, show that CD33 can be removed from HSCs without any deleterious impact on cell biology.

The in vivo study below shows engraftment of human HSCs into 15 immune-compromised mice, with 15 mice used as a vehicle treated control group. Following 16 weeks of engraftment, CD33Del eHSCs and CD33WT control cells differentiated into various classes of blood cells, which allowed detection of these cells and functional assays of differentiated cells. We observed statistically significant (p<0.0001) lower rates of CD33 surface proteins, suggesting successful genome engineering in CD33Del cells. As shown in the other figures below, we observed no statistically significant differences in the number of cells by cell type produced by the CD33WT and CD33Del HSCs.

16-week xeno-transplant mouse model engraftment data of human CD33-engineered cells

In order to observe the in vitro functionality of differentiated immune cells derived from eHSCs, we compared the ability of cells differentiated from CD33WT and CD33Del cells to phagocytose or produce cytokines. No differences in function were observed.

Cells derived from CD33Del eHSCs and CD33WT HSCs demonstrate intact functionality

In addition to data generated by us, academic laboratories at Columbia University, the University of Pennsylvania, and the Fred Hutchinson Cancer Research Center have each conducted similar experiments in vitro and in vivo with very similar findings, showing that no deleterious effects can be observed from replacing existing blood cells with CD33Del cells.

Preclinical Validation of CD33 Deletion in HSCs

While these preclinical data offer encouraging evidence of the non-essential nature of CD33, we believe the strongest support for our approach comes from existing human genetics data. We have found 65 individuals with homozygous loss of function mutations in the CD33 gene using the genetic database maintained by the Broad Institute. More recently, we identified 176 individuals with homozygous loss-of-function mutations in CD33 through the database maintained by the UK Biobank. This critical evidence suggests the non-essential nature of CD33 function in humans, and we published a white paper in January 2023 in Cell & Gene outlining our analysis of this data to inform our approach. We believe this finding of so-called “null mutants” among the adult human population, combined with the lack of discernable in vitro and in vivo effects observed with the removal of CD33, mitigates concerns associated with introducing CD33Del eHSCs in humans.

Trem-cel with Other Targeted Therapies

Mylotarg is currently the only anti-CD33 therapy approved by the FDA. We believe that other anti-CD33 therapies that are not yet approved, such as our VCAR33 product candidates or bispecific antibodies, may ultimately be better targeted therapies due to higher expected potency and target specificity. Different therapeutics may also be more suitable in various clinical settings and disease states. We therefore plan to support research and development efforts studying the benefits of trem-cel and other eHSC approaches with several targeted therapies using different treatment modalities. This strategy is intended to optimize the potential for trem-cel and other eHSC programs to eventually become a new standard of care in transplantation, unlocking the potential of multiple targeted therapies for patients with AML and other blood cancers.

Trem-cel and Myelodysplastic Syndrome and Myeloproliferative Neoplasm

Other blood cancers overexpress CD33, including myelodysplastic syndrome (“MDS”) and myeloproliferative neoplasms (“MPNs”). MDS consists of a spectrum of bone marrow cancers that are characterized by reduction in blood cell counts and an increase in immature blood cells in bone marrow. This condition evolves into AML in up to 30% of cases. Similarly, MPNs are a group of blood cancers such as chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis and essential thrombocythemia where excessive fully differentiated blood cells are produced by the bone marrow, and these conditions may also evolve into more aggressive AML. Patients with these conditions can be segmented into different risk categories based on cell counts and cytogenetics, with intermediate- or high-risk patients often treated with HSCT, and together MDS and MPN are the most common indications for allogeneic HSCT outside of AML. Scientific evidence produced by third parties shows that blast cells responsible for MDS and MPN express CD33 and other myeloid cell surface targets. We believe trem-cel has the potential to provide a therapeutic window that enables anti-CD33 therapies to be effective in

those settings, and we are exploring the potential use of trem-cel in combination with targeted therapies in these indications.

VCAR33 for the Treatment of Blood Cancers

Overview

VCAR33 is a CAR-T therapy designed to target CD33, a clinically-validated target for AML. VCAR33 uses a CAR moiety that recognizes CD33 on the outside of the cell surface using the huM195 CD33 binder. The same binder was used in lintuzumab, which is an agent that has been tested in clinical trials and demonstrated clinical activity. We licensed VCAR33 from the U.S. Department of Health and Human Services, as represented by National Cancer Institute (“NCI”) of the National Institutes of Health (“NIH”). We are studying VCAR33 with autologous and allogeneic cell sources.

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VCAR33ALLO uses allogeneic healthy donor-derived cells. There has been an increasing appreciation of the value of cell phenotype in CAR-T approaches, and the HLA-matched healthy donor cells are a potentially superior cell phenotype with improved persistence and in vivo expansion ability. We plan to submit an IND for this program in the first half of 2023 to support a Phase 1/2 clinical trial for patients with relapsed/refractory AML.

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VCAR33AUTO uses autologous cells from each patient and is being studied in an ongoing Phase 1/2 clinical trial sponsored by the NMDP in young adult and pediatric patients with relapsed/refractory AML in a bridge-to-transplant study. We have received cross-reference rights for the IND for the NMDP program. Timing of data release is dependent on the investigators conducting the trial.

Preclinical Proof of Concept

The NIH conducted preclinical studies to assess the ability of various CAR-T constructs, including a construct using the huM195 binder, to clear human AML tumor cells implanted in mice. These CAR-T constructs, as well as a saline solution and untransduced T cells used as controls, were administered to mice that were then observed over the course of a 10-week period. As shown in the figure below, the constructs containing the 4-1BB costimulatory domain were less active against the AML cells than those containing CD28. In addition, in other studies, the NIH noted toxicity signals in CAR constructs containing the hP67.6 binder, which is the same binder used in Mylotarg. As a result, the NIH chose to take the construct using the huM195 binder and CD28 costimulatory domain into clinical development.

Tumor cell clearance of CAR constructs in mouse xenograft models

VCAR33ALLO Clinical Development

We plan to study VCAR33ALLO in a Phase 1/2 clinical trial that will run in two phases: the first phase, which is expected to enroll approximately 12 patients, is designed to determine the maximum tolerated dose of VCAR33ALLO using a 3+3 trial design; the second phase, which is expected to enroll up to 12 patients, is an expansion phase designed to evaluate the rate of clinical response to treatment. VCAR33ALLO could cause bone marrow failure due to the elimination of normal hematopoiesis in the absence of an approach that limits on-target toxicity, and therefore, the clinical trial is studying VCAR33ALLO in the bridge-to-transplant setting, where bone marrow failure is manageable with subsequent transplant. Patients are monitored for safety endpoints associated with CAR-T therapy including evidence of cytokine release syndrome, hepatotoxicity and neurotoxicity. Since VCAR33ALLO uses T cells sourced from a healthy donor, there may be additional risk of these T cells attacking the patient called graft versus host disease, and incidence of this will be monitored in the trial. In addition, treatment-related mortality and time to engraftment, will be assessed post-HSCT to determine the safety of VCAR33ALLO in combination with the transplantation procedure. We plan to submit an IND for this clinical trial in the first half of 2023.

We anticipate the key clinical efficacy endpoints of the trial being the reduction of the blast count in the bone marrow to achieve a morphologic remission, assessment of the elimination of MRD by flow cytometry or molecular methods and the percent of patients consequently able to proceed to a potentially curative HSCT. Standard transplant-related outcomes of the trial including overall survival, relapse rates and event-free survival will be

measured. Exploratory objectives will assess VCAR33ALLO performance in patients including expansion and persistence within the blood and bone marrow.

Our Solution to Transform Patient Outcomes: The Trem-cel + VCAR33 Treatment System

We believe trem-cel could unlock the potential of anti-CD33 therapies that are much more potent than Mylotarg. We believe VCAR33ALLO could be a highly potent anticancer therapy that, when combined with trem-cel, would not be associated with severe myeloablative toxicities. We believe the trem-cel + VCAR33 Treatment System is a novel and comprehensive approach that has the potential to transform clinical outcomes and establish a new standard of care for patients suffering with AML.

An attractive feature of this Treatment System is to use the same allogeneic source of cells for both the eHSC and CAR-T. In this scenario, the apheresis product from the healthy donor can be processed to serve as starting materials for both products. One advantage of this approach is that donor-derived T cells should not recognize CAR-T cells as foreign, potentially prolonging persistence. In addition, sourcing T cells from healthy donors may provide a healthier, more abundant cell source, allowing for optimizations and efficiencies in the manufacturing process that are not possible with autologous sources. Unlike autologous CAR-T therapies, the manufacturing of the CAR-T cells would not be rate limiting when combined with trem-cel, as the CAR-T therapy would not be needed until 60 days after administration of trem-cel.

Trem-cel + VCAR33 Treatment System—Clinical Development

We intend to submit an IND application with the FDA and conduct a clinical trial of the trem-cel + VCAR33 Treatment System after we obtain the initial results from our trem-cel Phase 1/2a clinical trial and our planned VCAR33ALLO Phase 1/2 monotherapy clinical trial. We believe demonstration of disease clearance activity by VCAR33ALLO would provide a fundamental rationale for further development in a non-relapse/refractory population which is still high risk, including patients with poor prognostic molecular markers and/or MRD positivity. We would evaluate VCAR33ALLO in a post-trem-cel transplant setting to reduce the risk of recurrence or treat evidence of early relapse. Through use of trem-cel, we believe VCAR33ALLO could be used in a post-transplant maintenance setting since CD33 negative hematopoiesis established by the trem-cel graft would be protected from eradication. The objective of this trial would be to assess the safety and initial clinical efficacy of the trem-cel + VCAR33Treatment System.

Ongoing Preclinical Programs

We believe our approach can extend beyond CD33 where targets fulfill three important criteria: firstly, these targets are expressed on cancer cells; secondly, these targets are expressed on cells of hematopoietic lineage (and therefore present a safety concern); and lastly there is evidence these protein targets are biologically dispensable. We have generated preclinical data exploring targets such as CD123, EMR2, and CD5 which all currently show promise fulfilling these criteria.

Other Myeloid Targets: CD123, CLL-1, EMR2

CD123, CLL-1, and EMR2 are targets expressed strongly in various myeloid blood cancers including AML. These targets are expressed both in bulk AML cells as well as leukemic stem cells. As shown in the figure below, we have the ability to genetically engineer HSCs in human cells to remove expression of these targets with good efficiency. As such, we continue to research these targets as potential target candidates for our eHSCs and CAR-T therapies.

High Editing Frequency Observed in Human CD34+Cells for CD123, CLL-1 and EMR2

Multiplex Engineering: High Editing Efficiency Across CD123, CLL-1, and EMR2 Targets

Multiplex engineering is a strategy and method where multiple genetic targets are engineered within the same cells in the same manufacturing process. Multiplex engineering could allow removal or modification of two or more distinct genes, thus allowing for targeted therapies directed at two or more separate targets to be used in combination or in sequence, which could be particularly valuable to prevent escape mechanisms involving tumor cells down-regulating target expression.

We have developed several techniques for multiplex engineering HSCs. One such technique is sequential Cas9 editing, where HSPCs are subject to a two separate Cas9 edits separated by a defined time period in order to allow the first edit to complete before applying the second edit. This separation is important to avoid translocation errors, which are gene repairs resulting in one DNA segment joining other DNA segments from different parts of the same chromosome or segments of other chromosomes. As seen in the chart below left, we can efficiently knock out expression of both CD33 and CLL-1 from HSPCs using this technique.

Another technique involves a technology called base editing, which involves converting a specific DNA base into another at a targeted genomic locus. As such, base editing does not require a cut, lowering the risk of translocation errors. As seen in the chart on the below right, we can efficiently knock out expression of both CD33 and CLL-1 from HSPCs using a single base editing step.

Our expertise in multiplex engineering allowed us to make progress on a new program called the CD33-CLL1 Treatment System. This Treatment System is made up of the CD33-CLL1 multiplex-engineered eHSC and the CD33-CLL1 multi-specific CAR-T.

In vitro proof of concept for this approach is shown below. In this experiment we compared the survival of wild type, CD33Del, CLL-1Del and CD33Del+CLL-1Del cell lines when simultaneously exposed to CD33 and CLL-1 CAR-T treatments. We observed statistically significant higher survival of cell lines with protein removals corresponding to the CAR-T targets, with the highest survival in the cell line lacking both CD33 and CLL-1 surface targets. These results suggest that the removal of these surface targets provided protection of the cell lines from the target-specific effects of the CAR-T therapy.

A multiplex approach may provide advantages in two areas. Firstly, target expression can vary in tumor cells from the same patient, a phenomenon known as tumor heterogeneity. Applying therapies such as a multi-specific CAR-T may reduce that concern. Secondly, it is theoretically possible for tumor cells to downregulate expression of a target to avoid being killed, a phenomenon known as tumor escape. Again, pursuing multiple targets simultaneously may reduce the effectiveness of the tumor escape mechanism.

Survival of CD33Del and CLL-1Del cells after exposure to

anti-CD33 and anti-CLL-1 CAR-T therapies

Commercial Strategy and Reimbursement Framework for Our eHSCs and CAR-T Product Candidate

Given the potential value proposition of eHSCs enabling targeted therapies, our goal is to maximize the reach of our therapies, if approved, to all patients in the transplant setting suffering from blood cancers. Each year, approximately 42,500 new cases of AML are diagnosed across the United States (~20,000), Europe (~18,000) and Japan (~4,500). For the past 20 years, there has been an increasing trend in allogeneic transplants for AML. Currently, there are approximately 12,000 allogeneic HSCTs performed globally each year, with approximately 3,500 performed in the United States, 7,000 in Europe and 1,500 in Japan.

We believe we will be able to commercialize our eHSCs and targeted therapies, if approved, with a focused footprint where we can leverage the existing logistical infrastructure of the NMDP and HSC transplants centers. HSCTs are performed at tertiary medical care hospitals with specialized HSC transplant centers. The United States, EU5 and Japan have approximately 200, 300 and 185 transplant centers, respectively. The transplant volumes are further concentrated with 15%, or approximately 30 U.S. transplant centers, performing 50% of U.S. transplants. Building on a concentrated network of transplant centers, we have the added advantage of a rapid manufacturing process of <14 days. This turn-around time for collecting cells and shipping is a critical component of a successful commercialization.

As shown below, we believe that our platform and approach gives us the ability to transform the treatment paradigm for patients suffering from AML at each significant step in their journey by increasing transplant eligibility, replacing the standard of care for transplants, and unlocking the potential of targeted therapies post-transplant.

Opportunity to Transform the Patient Journey

We believe multiple reimbursement pathways may be available in the United States to capture the value of eHSCs and targeted therapies, such as CAR-T. Effective for cost reporting periods beginning on or after October 1, 2020, under the Hospital Inpatient Prospective Payment System (“IPPS”), Medicare payment for HSCT will include a carve-out for the actual cost of stem cell acquisition and processing, and payment will instead be made on a reasonable cost basis. We believe this new rule may apply to innovative sources of donor stem cells like eHSCs. In addition, a new Medicare Severity Diagnosis-Related Group (“MS-DRG”) establishes a base payment rate of approximately $248,000 for CAR-T cases.

A potential alternative reimbursement pathway for eHSC is Medicare New Technology Add-on Payment (“NTAP”) which, if approved, allows for temporary reimbursement for new cell therapies above the standard MS-DRG payment threshold. When certain criteria are met, the Centers for Medicare & Medicaid Services (“CMS”), the federal agency responsible for administering the Medicare program, may provide incremental reimbursement for up to 65% of the cost of therapy in addition to the standard MS-DRG payment. For patients covered by commercial insurance, we believe that reimbursement will be based on a case rate methodology with provisions for separate payments for new therapies such as eHSC. Lastly, risk-sharing agreements or value-based purchasing models is another option that is becoming more common with novel cell and gene therapies.

Potential Value Proposition and Reimbursement Pathways

License Agreements

Exclusive License Agreement with Columbia University

In April 2016, we entered into an exclusive license agreement with The Trustees of Columbia University in the City of New York (“Columbia”), which agreement was subsequently amended in February 2019 and November 2021 (the “Columbia Agreement”). Pursuant to the Columbia Agreement, we obtained a worldwide, exclusive license, with the right to grant sublicenses (subject to certain restrictions), under certain of Columbia’s patents, know-how and materials to discover, develop, manufacture, have made, use, sell, offer to sell, have sold, import, export, distribute, rent or lease products that are covered by such patents or involve the use of or otherwise incorporate such know-how or materials, in each case for any and all uses. The foregoing license is subject to certain customary retained rights of Columbia, including the right to conduct academic research and publish know-how. We are also obligated to use commercially reasonable efforts to research, discover, develop and market licensed products for commercial sale and distribution, including by achieving one or more specified diligence milestones.

Under the Columbia Agreement, we paid Columbia an upfront fee of $25,000 and issued to Columbia 91,911 shares of our common stock. We are also obligated to pay Columbia an annual fee in the low five digits, as well as royalties on net sales of products that are covered by the licensed patents ranging in the low single digits and on net sales of products that are not covered by the licensed patents but involve the use of or otherwise incorporate licensed know-how or materials ranging in the low single digits (which range is lower than the range for patented products), in each case with respect to such products sold by us but not our sublicensees. Royalties are payable on a patented product-by-patented product basis and country-by-country basis for such period as a valid claim covers such patented product in such country, which we expect to be until January 2040, absent any applicable patent term extensions, and, on an unpatented product-by-unpatented product and country-by-country basis for the longer of ten years from first commercial sale of such unpatented product in such country or expiration of any market exclusivity for such unpatented product in such country. If the royalty term for a patented product expires in a country and such product would otherwise qualify as an unpatented product in such country (and the applicable royalty term for such unpatented product has yet to expire in such country), then we are obligated to pay Columbia royalties for such unpatented product for the remainder of the royalty term in such country. Additionally, we are obligated to pay Columbia up to $4.45 million in the aggregate for certain clinical, regulatory and commercial milestones for the first two products, $2.0 million in the aggregate for certain commercial milestones for a single additional product incorporating certain of the intellectual property licensed to us under the Columbia Agreement and a mid-second decile percentage of consideration received from sublicensees, including royalties, provided that if such sublicensing income includes a milestone payment for which we are already obligated to make a milestone payment under the Columbia Agreement, then Columbia shall only be entitled to the higher of our milestone payment and its portion of the sublicensing income.

The Columbia Agreement expires on a country-by-country and product-by-product basis upon expiration of the applicable royalty term for such product in such country. Columbia may either terminate the Columbia Agreement or convert our license to a non-exclusive license in the case of our insolvency, or upon our uncured material breach of the agreement of certain specified provisions, including in the event that we fail to achieve one or more specified diligence milestone(s) and fail to mutually agree upon a revised plan for development of a licensed product. Additionally, we have the right to terminate the Columbia Agreement at any time upon specified written notice to Columbia.

Exclusive License Agreement with National Institutes of Health

In October 2020, we entered into a patent license agreement (the “Patent License”) with the U.S. Department of Health and Human Services, as represented by National Cancer Institute (“NCI”) of the NIH. Pursuant to the Patent License, we hold an exclusive, worldwide license, sublicensable with the prior written consent of NIH, to certain intellectual property rights to develop, manufacture and commercialize licensed products, or to practice licensed processes, in each case, for use in the development of a CAR therapy mono-specific for CD33 for the prophylaxis or treatment of CD33-expressing hematological malignancies (but excluding CD33-specific logic-gated CAR-based immunotherapies) wherein the CAR is comprised of the CD33-binding domain referenced as Hu195 or hP67.6, is delivered via lentiviral transduction, and the T cells are derived from the patient or from an allogeneic source, which we collectively refer to as the field of use.

Pursuant to the terms of the Patent License, we are required to pay NCI a license issue fee in the aggregate amount of $400,000. The terms of the Patent License also require us to pay NCI de minimis minimum annual royalties, which royalties are creditable against earned royalties on sales of licensed products or licensed processes. We must also pay NCI tiered royalties on net sales of licensed products at rates ranging in the low single digits if the product CAR-T cells are derived from the patient, and at a higher range of rates in the low single digits if the product CAR-T cells are derived from an allogeneic source. Such royalties are payable on a licensed product-by-licensed product and country-by-country basis, commencing on the date of first commercial sale of such licensed product in such country, until the date such licensed product ceases to be covered by a valid claim of a licensed patent in such country, which we expect to occur in March 2039, absent any applicable patent term extensions, and are subject to reduction for unblocking licenses from third parties, subject to a specified royalty floor.

We are required to pay NCI one-time milestone payments upon successful completion of specified clinical and regulatory milestones relating to the licensed products. The aggregate potential milestone payments are $8.0 million. In addition, we are required to pay NCI one-time milestone payments following aggregate net sales of licensed products at certain net sales up to $2.0 billion. The aggregate potential amount of these milestone payments is $6.0 million. To the extent we enter into a sublicensing agreement relating to a licensed product, we are required to pay NCI a percentage of the non-royalty based consideration received from a sublicensee, with specified exclusions, which percentage ranges from the low single digits to low double digits, depending on the stage of development of the licensed product at the time of the sublicense. We are also required to reimburse NCI for its past patent expenses for the licensed patent rights, with such amounts being payable in three installments during the term of the Patent License, as well as our pro rata share of future patent expenses, in each case, in connection with NCI’s prosecution or maintenance of the licensed patent rights. We have the right to surrender our license rights in any country and will not be required to pay NCI for patent prosecution or maintenance expenses for any licensed patents for which we exercise such right.

We are required under the Patent License to use reasonable commercial efforts to bring the licensed products and licensed processes to practical application, which includes adhering to an agreed upon commercial development plan and meeting certain performance benchmarks. We are also required, commencing upon first commercial sale of a licensed product and for the remainder of the term of the Patent License, to use reasonable commercial efforts to make licensed products and licensed processes reasonably accessible to the U.S. public.

The Patent License will expire upon expiration of the last valid claim of a licensed patent, unless terminated earlier as described below. NCI may terminate the Patent License in the event of a material breach, including if we do not use reasonable commercial efforts to execute the commercial development plan, or if we do not achieve the performance milestones by certain dates, following the expiration of a 90-day notice period during which we must ether cure the relevant breach or initiate corrective action to NCI’s reasonable satisfaction. We may terminate the Patent License, in its entirety or with respect to any license in any country, in our sole discretion at any time upon 60 days’ written notice to NCI. In addition, NCI has the right to require us to grant sublicenses under the licensed

patent rights in any of the fields of use under specified conditions, if required by public health or safety concerns, or to terminate or modify the Patent License if deemed necessary to meet requirements for public use as specified by federal regulations, if NCI determines that we are not reasonably satisfying such requirements.

We cannot assign the Patent License without NCI’s prior written consent, other than to our affiliates. Upon NCI’s approval of a proposed assignment, we must pay NCI a low-single digit percentage of the fair market value of any consideration we receive for such assignment.

Sales and Marketing

Given our stage of development, we have not yet established a commercial organization or distribution capabilities. We plan to build focused capabilities in the United States to commercialize our development programs focused on eHSCs and targeted therapies, where we believe the patient populations and medical specialists for the indications we are targeting are sufficiently concentrated to allow us to effectively promote our products, if approved for commercial sale, with a targeted sales team. In other markets for which commercialization may be less capital efficient where the patient populations and medical specialists are less concentrated we may selectively pursue strategic collaborations with third parties in order to maximize the commercial potential of our product candidates.

Manufacturing

We operate an in-house clinical manufacturing facility in Cambridge, Massachusetts to support development of our eHSC and CAR-T therapeutic candidates for patients with blood cancers. The facility is located in the same premises as our headquarters, in Cambridge, MA. We have designed the facility to support clinical manufacturing for our eHSC and cell therapy programs and to be cGMP compliant. By integrating our internal research, process development, analytical development, manufacturing, and quality control testing capabilities under one roof, we believe we can achieve flexible manufacturing capacity and reduce the time and cost required to manufacture our complex cell therapy clinical candidates. While this facility is now operational, we continue to rely on third-party contract manufacturers for our required raw materials, manufacturing devices, active pharmaceutical ingredients and finished product for our research and clinical manufacturing. We do not have long-term agreements with any of these third parties. We also do not have any current contractual relationship for the manufacture of material for clinical trials beyond Phase 1/2a or commercial supplies. We intend to enter into agreements with third-party contract manufacturers and one or more backup manufacturers for future production. Although we are developing certain in-house manufacturing capabilities for our current clinical needs, we continue to analyze the feasibility of building additional manufacturing capabilities for future development and commercial quantities of any products that we develop. Such products will need to be manufactured in facilities, and by processes, that comply with the requirements of the FDA and the regulatory agencies of other jurisdictions in which we are seeking approval.

Competition

The biotechnology industry is characterized by intense and dynamic competition to develop new technologies and proprietary therapies. Any product candidates that we successfully develop and commercialize will have to compete with existing therapies and new therapies that may become available in the future. We believe that our technology platform and our scientific and clinical expertise may provide us with competitive advantages. However, we face potential competition from various sources, including larger and better-funded pharmaceutical, specialty pharmaceutical and biotechnology companies, as well as from academic institutions, governmental agencies and public and private research institutions. Prior to approval, these entities may compete with us in hiring scientific and management personnel, establishing clinical study sites, recruiting patients to participate in clinical trials and acquiring technologies complementary to, or necessary for, our programs. Furthermore, key competitive factors will affect the success of any product that may be approved by regulators, including the efficacy, safety profile, pricing, method of administration and level of promotional activity of such product.

In the case of our lead eHSC product candidate, trem-cel, we are not aware of any approved products in development that apply gene engineering technology to donor HSCs in order to reduce the on-target toxicity of targeted cancer therapies. However, Cimeio Therapeutics is a private company that is pursuing a “cell-shielding technology” with “paired immunotherapies” approach to improve HSCTs that could be competitive although there are no known pipeline candidates for CD33. Researchers at the University of Pennsylvania (“UPenn”) have

published the results of academic studies on gene engineering HSCs for this purpose, and UPenn has licensed intellectual property related to this approach to Tmunity Therapeutics Incorporated who merged with Kite Pharma in 2022. UPenn, Dana Farber, Heidelberg University Hospital and Beam Therapeutics have presented preclinical research engineering HSCs paired with a targeted therapy as a HSCT conditioning approach and/or treatment for hematopoietic malignancies. We are also aware of many companies that are attempting to address the problem of on-target toxicity through other treatment modalities, by attempting to improve the specificity of targeted therapies, including CD33-directed targeted therapies, for AML and other hematological cancer cells. For example, Johnson & Johnson and Amgen Inc. have CD33-directed bispecific antibodies in Phase 1 clinical development. There are also regulatable CD33 CAR-Ts being pursued by 2seventy bio, AvenCell, Aleta Biotherapeutics and Senti Biosciences. If any of these companies successfully develop effective targeted therapies for hematological malignancies without significant on-target toxicity, we believe they could compete with our eHSCs, including trem-cel.

In the case of VCAR33, there are several companies exploring CAR-T therapies in early trials for relapsed/refractory AML. City of Hope has opened a Phase 1 clinical trial treating relapsed/refractory AML using patient-specific donor-derived (allogeneic) CD33-CAR T cells which is a similar approach to VCAR33ALLO using donor-derived (allogeneic) CD33-CAR-Ts post-transplant. There are also a number of autologous CAR-Ts in clinical phase development to treat relapsed/refractory AML, including Precigen, Inc., which is studying the CD33 target; Kite Pharma and Baylor College are studying CLL-1; St. Jude Children's Hospital, UPenn, Mustang Bio, Inc. and Cellectis S.A. are investigating CAR-T therapies targeting CD123. There are also a number of CAR-T clinical studies open in China. Dual targeting CAR-T cell-based approaches are also being studied by iCell Gene Therapeutics, LLC, Guangzhou Bio-Gene and Legend Biotech Corporation, each of which target both CD33 and CLL-1.

Beyond CAR-T therapies, a number of small molecule and monoclonal antibody products have been approved in recent years for the treatment of AML, including Novartis International AG’s Rydapt (midostaurin), Jazz Pharmaceuticals plc’s Vyxeos (daunorubicin and cytarabine), Bristol-Myers Squibb Company’s Idhifa (enasidenib), Pfizer Inc.’s Mylotarg (gemtuzumab ozogamicin) and Daurismo (glasdegib), Agios Pharmaceuticals Inc.’s Tibsovo (ivosidenib), Astella Pharma Inc.’s Xospata (gilteritinib), and AbbVie Inc.’s Venclexta (venetoclax). Other treatment modalities, such as bispecific antibodies and antibody-drug conjugates are also in development across a wide range of targets. In addition, marketed therapies are being studied in the relapsed/refractory setting, including Bristol-Myers Squibb Company’s CC-486 oral formulation of azacitidine and AbbVie Inc.’s venetoclax.

Many of our current or potential competitors have substantially greater financial, technical and human resources. Accordingly, our competitors may be more successful in developing or marketing products and technologies that are more effective, safer or less costly. Additionally, our competitors may obtain regulatory approval for their products more rapidly and may achieve more widespread market acceptance. Future collaborations and mergers and acquisitions may result in further resource concentration among a smaller number of competitors. Smaller or early-stage companies may also prove to be significant competitors, either alone or through collaborative arrangements with large and established companies.

Intellectual Property

Overview

We strive to protect the proprietary product candidates and technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the composition of matter of our product candidates, their methods of use, their methods of production, related technologies and other inventions. In addition to patent protection, we also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection, including certain aspects of technical know-how.

Our commercial success depends in part upon our ability to obtain and maintain patent and other proprietary protection for commercially important technologies, inventions and know-how related to our business, defend and enforce our intellectual property rights, particularly our patent rights, preserve the confidentiality of our trade secrets and operate without infringing valid and enforceable intellectual property rights of others.

The patent positions for biopharmaceutical companies like us are generally uncertain and can involve complex legal, scientific and factual issues. In addition, the coverage claimed in a patent application can be significantly reduced before a patent is issued, and its scope can be reinterpreted and even challenged after issuance.

As a result, we cannot guarantee that any of our product candidates will be protectable or remain protected by enforceable patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or invalidated by third parties.

As of March 21, 2023, our owned patent portfolio is composed of more than 90 pending U.S. and foreign patent applications, approximately 8 pending U.S. provisional patent applications, and 6 granted U.S. patents. In addition, we have licensed 8 granted U.S. and foreign patents, and approximately 55 pending patent applications in the United States and foreign jurisdictions.

Patent Rights Relating to Our eHSC Programs

The patent portfolio related to our lead eHSC product candidate, trem-cel (formerly VOR33), includes four patent families that are exclusively licensed from Columbia. The first patent family licensed from Columbia is directed to compositions and methods for gene engineering lineage-specific cell surface antigens, such as CD33, in HSCs and use thereof, and includes eight granted U.S. and foreign patents, two pending U.S. applications and at least 13 pending foreign applications in Europe, Japan, Canada, China, Australia and other jurisdictions. Any patents that grant from applications claiming priority to this patent family would be expected to expire in 2036, absent any applicable patent term extensions.

As of March 21, 2023, the second patent family licensed from Columbia, directed to compositions and methods of use of HSCs containing a single nucleotide polymorphism in CD33, includes an allowed U.S. application and two pending foreign applications in Europe and Japan. Any patents that grant from applications claiming priority to this patent family would be expected to expire in 2038, absent any applicable patent term extensions.

As of March 21, 2023, the third patent family licensed from Columbia, directed to compositions and methods for gene engineering CD33 in HSCs and use thereof, includes a pending U.S. application and at least 14 pending foreign applications in Europe, Japan, Canada, China, Australia and other jurisdictions. Any patents that grant from applications claiming priority to this patent family would be expected to expire in 2040, absent any applicable patent term extensions.

As of March 21, 2023, the fourth patent family licensed from Columbia, directed to compositions and methods for inhibition of lineage-specific cell antigens using CRISPR-based base editor systems in HSCs and use thereof, includes a pending U.S. application and at least 8 pending foreign applications in Europe, Japan, Canada, China, Australia and other jurisdictions. Any patents that grant from applications claiming priority to this patent family would be expected to expire in 2041, absent any applicable patent term extensions.

The patent portfolio related to trem-cel also includes three patent families that we own. As of March 21, 2023, the first family, directed to compositions and methods of engineering lineage-specific antigens in HSCs includes one pending patent application in the United States and 14 pending foreign applications in Europe, Japan, Canada, China, Australia and other jurisdictions. Any patents that grant from applications claiming priority to this patent family would be expected to expire in 2038, absent any applicable patent term extensions. As of March 21, 2023, the second family, directed to compositions and methods of engineering multiple lineage-specific antigens in HSCs, includes six U.S. patents, three pending U.S. patent applications and at least 15 pending foreign patent applications. Any patents that grant from applications within these families would be expected to expire in 2039, absent any applicable patent term extensions. As of March 21, 2023, the third family, directed to compositions and methods of treating a hematopoietic malignancy, includes a pending Patent Cooperation Treaty (“PCT”) patent application. Any patents that grant from applications within this family would be expected to expire in 2041, absent any applicable patent term extensions.

We also own three patent families directed to compositions and methods of engineering specific antigens in HSCs, including CD33, CLL-1 and CD123. As of March 21, 2023, the first family, directed to compositions and methods for engineering CD33 in HSCs includes one pending U.S. application and eight pending foreign patent applications. As of March 21, 2023, the second family, directed to compositions and methods for engineering CLL-1

in HSCs includes one pending U.S. application and eleven pending foreign patent applications. As of March 21, 2023, the third family, directed to compositions and methods for engineering CD123 in HSCs includes one pending U.S. application and 11 pending foreign applications.

We also own eight patent families directed to compositions and methods of engineering additional target antigens in HSCs. These families include five pending PCT applications, three pending U.S. applications and five pending foreign patent applications. Any patents that grant from applications within these families would be expected to expire in 2041 or 2042, absent any applicable patent term extensions.

Patent Rights Relating to Our Targeted Therapy Programs

We own three patent families directed to compositions and methods of making and using CARs. As of March 21, 2023, two of these families each include one pending PCT application and one family includes one pending U.S. application and two pending foreign patent applications, and any patents that grant from applications in these families would be expected to expire in 2041, absent any applicable patent term extensions.

We have one patent family that is exclusively licensed from the NIH related to our VCAR33 program. As of March 21, 2023, the patent family licensed from NCI is directed to CARs targeting CD33, compositions containing cells expressing CARs, and methods of use thereof, and includes one pending U.S. application and at least 14 pending foreign applications in Europe, Japan, Canada, China, Australia and other countries. Any patents that grant from applications in this patent family would be expected to expire in 2039, absent any applicable patent term extensions.

We own one patent family directed to compositions and methods of using single domain antibodies targeting CD33. As of March 21 2023, this family includes one pending U.S. patent application and six pending foreign patent applications, any patents that grant from applications in this family would be expected to expire in 2041, absent any applicable patent term extensions.

Provisional Patent Applications

As indicated above, some of our owned patent applications are provisional patent applications. Provisional patent applications are not eligible to become issued patents until, among other things, we file a non-provisional patent application within 12 months of filing of one or more of our related provisional patent applications. If we do not timely file any non-provisional patent applications, we may lose our priority date with respect to our provisional patent applications and any patent protection on the inventions disclosed in our provisional patent applications. While we intend to timely file non-provisional patent applications relating to our provisional patent applications, we cannot predict whether any such patent applications will result in the issuance of patents that provide us with any competitive advantage. Moreover, the patent application and approval process is expensive and time-consuming. We may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner.

Patent Term and Term Extensions

The term of individual patents depends upon the legal term for patents in the countries in which they are obtained. In most countries in which we have filed, including the United States, the patent term is 20 years from the earliest filing date of a non-provisional patent application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted for a portion of the term effectively lost as a result of the FDA regulatory review period, subject to certain limitations and provided statutory and regulatory requirements are met. Any such patent term extension can be for no more than five years, only one patent per approved product can be extended, the extension cannot extend the total patent term beyond 14 years from FDA approval, and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. We may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. In the future, if and when our product candidates receive approval from the FDA or foreign regulatory authorities, we

expect to apply for patent term extensions on issued patents we may obtain in the future covering those products, depending upon the length of the clinical trials for each product and other factors. There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our product candidates will depend on our success in obtaining effective patent claims and enforcing those claims if granted. However, our owned and licensed pending patent applications, and any patent applications that we may in the future file or license from third parties may not result in the issuance of patents. We also cannot predict the breadth of claims that may be allowed or enforced in our patents. Any issued patents that we may receive in the future may be challenged, invalidated, infringed or circumvented. In addition, because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby limiting the protection such patent would afford the respective product and any competitive advantage such patent may provide. For more information, see the section entitled “Risk Factors—Risks Related to Intellectual Property.”

Other IP Rights

In addition to patents, we rely upon unpatented trade secrets and know-how, continuing technological innovation and confidential information to develop and maintain our proprietary position and protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection, including our proprietary processes for generating and propagating eHSCs. However, trade secrets and know-how can be difficult to protect. We seek to protect our proprietary information, in part, by executing confidentiality agreements with our collaborators and scientific advisors, and non-competition, non-solicitation, confidentiality and invention assignment agreements with our employees and consultants. We have also executed agreements requiring assignment of inventions with selected scientific advisors and collaborators. The confidentiality agreements we enter into are designed to protect our proprietary information and the agreements or clauses requiring assignment of inventions to us are designed to grant us ownership of technologies that are developed through our relationship with the respective counterparty. We cannot guarantee, however, that we have executed such agreements with all applicable counterparties, such agreements will not be breached, or that these agreements will afford us adequate protection of our intellectual property and proprietary rights. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our commercial partners, collaborators, employees and consultants use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions. For more information, see the section entitled “Risk Factors—Risks Related to Our Intellectual Property” in Part I, Item 1A of this Annual Report.

Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, or our drugs or processes, obtain licenses or cease certain activities. Our breach of any license agreements or failure to obtain a license to proprietary rights that we may require to develop or commercialize our future drugs may have an adverse impact on us. Since patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months or potentially longer, and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries, we cannot be certain of the priority of inventions covered by pending patent applications.

Trademarks

We also aim to obtain and maintain registration for trademarks that we consider are relevant to our business. As of March 21, 2023, we have filed for registration of the trademarks for VOR BIOPHARMA, for VOR33, for VOR, for our "V" logo, and for VOR BIO, for international class 5 (pharmaceuticals) under the Madrid Protocol, with more than 50 applications in the United States and foreign jurisdictions. We plan to register additional trademarks in connection with any future pharmaceutical products we may commercialize, if approved.

Government Regulation and Product Approval

As a biopharmaceutical company that operates in the United States, we are subject to extensive regulation. Our cell product candidates will be regulated as biologics. With this classification, commercial production of our product candidates will need to occur in registered facilities in compliance with current good manufacturing

practices (“cGMP”) for biologics. The FDA categorizes human cell- or tissue-based products as either minimally manipulated or more than minimally manipulated and has determined that more than minimally manipulated products require clinical trials to demonstrate product safety and efficacy and the submission of a Biologics License Application (“BLA”) for marketing authorization. Our product candidates are considered more than minimally manipulated and will require evaluation in clinical trials and the submission and approval of a BLA before we can market them.

The FDA and other government authorities in the United States (at the federal, state and local levels) and in other countries extensively regulate, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of biopharmaceutical products such as those we are developing. Our product candidates must be approved by the FDA before they may be legally marketed in the United States and by the appropriate foreign regulatory agency before they may be legally marketed in foreign countries. Generally, our activities in other countries will be subject to regulation that is similar in nature and scope as that imposed in the United States, although there can be important differences. Additionally, some significant aspects of regulation in Europe are addressed in a centralized way, but country-specific regulation remains essential in many respects. The process for obtaining regulatory marketing approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

U.S. Product Development Process

In the United States, the FDA regulates pharmaceutical and biological products under the Federal Food, Drug and Cosmetic Act, the Public Health Service Act (“PHSA”) and their implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial sanctions. FDA sanctions could include, among other actions, refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us. The process required by the FDA before a biological product may be marketed in the United States generally involves the following:

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completion of nonclinical laboratory tests and animal studies according to FDA’s good laboratory practices (“GLPs”) and applicable requirements for the humane use of laboratory animals or other applicable regulations;

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submission to the FDA of an IND application, which must become effective before human clinical trials may begin;

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approval by an independent Institutional Review Board (“IRB”) or ethics committee at each clinical site before the trial is commenced;

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performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practices (“GCPs”) and any additional requirements for the protection of human research patients and their health information, to establish the safety and efficacy of the proposed biological product for its intended use;

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submission to the FDA of a Biologics License Application (“BLA”) for marketing approval that includes substantial evidence of safety, efficacy, purity and potency from results of nonclinical testing and clinical trials;

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satisfactory completion of an FDA Advisory Committee review, if applicable;

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satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with cGMP, to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, potency, quality and purity

and, if applicable, the FDA’s current good tissue practices (“GTPs”) for the use of human cellular and tissue products;

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potential FDA audit of the nonclinical GLP study and clinical investigators and clinical trial sites that generated the data in support of the BLA; and

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FDA review and approval of the BLA and licensure of the manufacturing facility to permit commercial marketing of the product for particular indications for use in the United States.

Before testing any biological product candidate, including our product candidates, in humans, the product candidate enters the preclinical testing stage. Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies to assess the potential safety, biodistribution and activity of the product candidate. The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs. The clinical trial sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. Some preclinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the trial on a clinical hold within that 30-day time period. In such a case, the IND sponsor must resolve any outstanding concerns of the FDA before the clinical trial can begin. The FDA may also impose clinical holds on a biological product candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA. Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that, once begun, issues will not arise that suspend or terminate such trials.

Supervision of human gene transfer trials includes evaluation and assessment by an Institutional Biosafety Committee (“IBC”), a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution, as set forth in the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (“NIH Guidelines”). The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial. While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

Clinical trials involve the administration of the biological product candidate to human subjects under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur. Each protocol and any amendments to the protocol must be submitted to the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP requirements, including the requirement that all research patients provide informed consent. Further, each clinical trial must be reviewed and approved by an independent IRB at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. Certain clinical trials involving human gene transfer research also must be overseen by an IBC, a standing committee established specifically to provide peer review of the safety of research plans, procedures, personnel training and environmental risks of work involving recombinant DNA molecules. IBCs are typically assigned certain review responsibilities relating to the use of recombinant DNA molecules, including reviewing potential environmental risks, assessing containment levels, and evaluating the adequacy of facilities, personnel training and compliance with the NIH Guidelines. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no

demonstration of efficacy. There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Phase 1. The biological product candidate is initially introduced into healthy human subjects and tested for safety. In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients. The Center for Biological Research and Review has determined that healthy volunteers are not to receive any cell or gene therapy products in a Phase 1 trial because there are risks associated with these products and the effects may not be able to be evaluated in these healthy individuals. As a result, the recruitment of patients, the prolonger persistence of these therapies can prolong this phase of development in determining dose levels.

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Phase 2. The biological product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.

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Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efficacy, potency and safety in an expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk to benefit ratio of the product candidate and provide an adequate basis for product labeling.

Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up. These Phase 4 studies may be made a condition to approval of the BLA. During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA, and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human patients, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor or its data safety monitoring board may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research patients are being exposed to an unacceptable health risk, including risks inferred from other related or unrelated gene and cell therapy trials. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the biological product has been associated with unexpected serious harm to patients. In addition, some clinical trials are overseen by an independent group of qualified experts organized by the sponsor, known as a data safety monitoring board or committee. Depending on its charter, this group may determine whether a trial may move forward at designated check points based on access to certain data from the trial.

Gene therapy products are a new category of therapeutics. Because this is a relatively new and expanding area of novel therapeutic interventions, there can be no assurance as to the length of the trial period, the number of patients the FDA will require to be enrolled in the trials in order to establish the safety, efficacy, purity and potency of gene therapy products, or that the data generated in these trials will be acceptable to the FDA to support marketing approval.

Concurrently with clinical trials, companies usually complete additional studies and must also develop additional information about the physical characteristics of the biological product candidate as well as finalize a process for manufacturing the product candidate in commercial quantities in accordance with cGMP requirements. To help reduce the risk of the introduction of adventitious agents with use of biological products, the PHSA emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing quality batches of the product candidate and,

among other things, the sponsor must develop methods that are fully validated for testing the identity, strength, quality, potency and purity of the final biological product candidate. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the biological product candidate does not undergo unacceptable deterioration over its shelf life. Ensuring that the manufacturing process is robust and suitable to pass an FDA pre-approval inspection for a BLA is resource-intensive and requires sufficient time to prepare. Process improvement steps taken before, during and after a pivotal trial may also require a comparability protocol that would need to be conducted and reviewed by FDA.

U.S. Review and Approval Processes

After the completion of clinical trials of a biological product candidate, FDA approval of a BLA must be obtained before commercial marketing of the biological product. The BLA submission must include all relevant data of product development, laboratory and animal studies, human trials, information on the manufacture and composition of the product, proposed labeling and other relevant information. The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.

Under the Prescription Drug User Fee Act, as amended (“PDUFA”), each BLA must be accompanied by a significant user fee. The FDA adjusts the PDUFA user fees on an annual basis. PDUFA also imposes an annual program fee for biological products. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA. The FDA reviews the BLA to determine, among other things, whether the proposed product is safe, potent and/or effective for its intended use and has an acceptable purity profile, and whether the product candidate is being manufactured in accordance with cGMP to assure and preserve the product candidate’s identity, safety, strength, quality, potency and purity. The FDA may refer applications for novel biological product candidates or biological product candidates that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions. During the biological product candidate approval process, the FDA also will determine whether a Risk Evaluation and Mitigation Strategy (“REMS”) is necessary to assure the safe use of the biological product candidate. A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. If the FDA concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS. The FDA will not approve a BLA without a REMS, if required.

Before approving a BLA, the FDA will inspect the facilities at which the product candidate is manufactured. The FDA will not approve the product candidate unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product candidate within required specifications. For immunotherapy product candidates, the FDA also will not approve the product candidate if the manufacturer is not in compliance with GTPs, to the extent applicable. These are FDA regulations and guidance documents that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissue and cellular and tissue based products (“HCT/Ps”), which are human cells or tissue intended for implantation, transplant, infusion or transfer into a human recipient. The primary intent of the GTP requirements is to ensure that cell and tissue based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable disease. FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, when applicable, to evaluate donors through screening and testing. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND trial requirements and GCP requirements. To assure cGMP,

GTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control.

Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the BLA does not satisfy its regulatory criteria for approval and deny approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. If the agency decides not to approve the BLA in its present form, the FDA will issue a complete response letter that describes all of the specific deficiencies in the BLA identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials. Additionally, the complete response letter may include recommended actions that the applicant might take to place the application in a condition for approval. If a complete response letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

If a product receives regulatory approval, the approval may be limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling. The FDA also may require a ‘Black Box Warning’ for noting serious adverse effects or other critical warnings regarding the use of the product. The FDA may impose restrictions and conditions on product distribution, prescribing or dispensing in the form of a risk management plan, a more formal REMS requirement or otherwise limit the scope of any approval. In addition, the FDA may require post marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess a biological product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.

In addition, under the Pediatric Research Equity Act (“PREA”), a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any product for an indication for which orphan designation has been granted. However, if only one indication for a product has orphan designation, a pediatric assessment may still be required for any applications to market that same product for the non-orphan indication(s).

Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug or biologic for this type of disease or condition will be recovered from sales in the United States for that drug or biologic. Orphan drug designation must be requested before submitting a BLA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. The orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

If a product candidate that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity. Orphan drug exclusivity does not prevent FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition. Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the BLA application user fee.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation. In addition, exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective, if the second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity, or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition. Orphan drug designation may also entitle a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.

Expedited Development and Review Programs

The FDA has established certain programs intended to expedite or facilitate the process for developing, reviewing or approving new products that meet certain criteria, including fast track designation, breakthrough therapy designation, accelerated approval and priority review. Specifically, new product candidates are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to the combination of the product candidate and the specific indication for which it is being studied. Unique to a fast track product, the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA and the payment of applicable user fees, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA.

Any product candidate submitted to the FDA for approval, including a product candidate with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. A product candidate is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease compared to marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for a new product candidate designated for priority review in an effort to facilitate the review.

Additionally, a product candidate may be eligible for accelerated approval. Product candidates studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA may require that a sponsor of a drug or biological product candidate receiving accelerated approval perform adequate and well-controlled post-marketing clinical studies. The FDA may withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product candidate. Also, there is the possibility that reimbursement by certain federal programs in the future may be reduced for products that receive accelerated approval.

Breakthrough therapy designation is intended to expedite the development and review of product candidates that treat serious or life-threatening conditions. The designation by FDA requires preliminary clinical evidence that a product candidate, alone or in combination with other drugs and biologics, demonstrates substantial improvement over currently available therapy on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If the FDA designates a breakthrough therapy, it may take actions appropriate to expedite the development and review of the application, which may include holding meetings with the sponsor and the review team throughout the development of the therapy; providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable; involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review; assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor; and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller trials or more efficient trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment. Breakthrough therapy designation comes with all of the benefits of fast-track designation, which means that the sponsor may file sections of the BLA for review on a rolling basis if certain conditions are satisfied, including an agreement with FDA on the proposed schedule for submission of portions of the application and the payment of applicable user fees before the FDA may initiate a review. The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same product candidate if relevant criteria are met. If a product candidate is designated as breakthrough therapy, FDA will expedite the development and review of such product candidate.

Specifically for cell and gene therapy products, a Regenerative Medicine Advanced Therapy ("RMAT") designation may be granted by FDA. It is a process designed to facilitate the development and expedite the review of such products to treat serious conditions and fill an unmet medical need. The criteria for the RMAT designation includes the following: a product that is intended to treat a serious condition, addresses an unmet medical need, and has clinical data demonstrating the product has the potential to address this unmet medical need.

Fast Track designation, priority review, accelerated approval, RMAT and breakthrough therapy designations do not change the standards for approval but may expedite the development or approval process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or that the time period for FDA review and approval will not be shortened.

Post-Approval Requirements

Any products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, continuing user fee requirements, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved uses (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet. Although a physician may prescribe a legally available product for an off-label use, if the physician deems such product to be appropriate in his/her professional medical judgment, a manufacturer may not market or promote off-label uses. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labeling. A company that is found to have promoted off-label use of its product may be subject to significant liability, including administrative, civil and criminal sanctions.

In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements after approval to ensure the long-term stability of the product. cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP. Manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP compliance. Discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved BLA, including, among other things, recall or withdrawal of the product from the market. In addition, changes to the manufacturing process are strictly regulated and, depending on the significance of the change, may require prior FDA approval before being implemented. Other types of changes to the approved product, such as adding new indications and claims, are also subject to further FDA review and approval.

The FDA also may require post-marketing testing, known as Phase 4 testing, and surveillance to monitor the effects of an approved product. Discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative consequences, including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties, among others. Newly discovered or developed safety or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures. Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks; or

imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of a product, complete withdrawal of the product from the market or product recalls;

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fines, warning letters or holds on post-approval clinical studies;

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refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of existing product approvals;

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product seizure or detention, or refusal of the FDA to permit the import or export of products;

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consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

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mandated modification of promotional materials and labeling and the issuance of corrective information;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or

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injunctions or the imposition of civil or criminal penalties.

U.S. Marketing Exclusivity

The Biologics Price Competition and Innovation Act (“BPCIA”) amended the PHSA to authorize the FDA to approve similar versions of innovative biologics, commonly known as biosimilars. A competitor seeking approval of a biosimilar must file an application to establish its molecule as highly similar to an approved innovator biologic, among other requirements.

Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical study or studies. Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic. Complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles to implementation of the abbreviated approval pathway that are still being worked out by the FDA.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA. In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed. During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well controlled clinical trials to demonstrate the safety, purity and potency of its product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

The BPCIA is complex and continues to be interpreted and implemented by the FDA. In addition, recent government proposals have sought to reduce the 12-year reference product exclusivity period. Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation. As a result, the ultimate impact, implementation, and impact of the BPCIA is subject to significant uncertainty.

Pediatric exclusivity is another type of regulatory market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

Other U.S. Healthcare Laws and Compliance Requirements

In the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the CMS, other divisions of the U.S. Department of Health and Human Services (e.g., the Office of Inspector General), the U.S. Department of Justice (“DOJ”) and individual U.S. Attorney offices within the DOJ, and state and local governments. For example, our business practices, including our clinical research and any future sales, marketing and scientific/educational grant programs may be required to comply with the fraud and abuse provisions of the Social Security Act, the false claims laws, the data privacy and security provisions of the Health Insurance Portability and Accountability Act (“HIPAA”), federal transparency requirements and similar state laws, each as amended.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for, either the referral of an individual for, or the purchasing, leasing, ordering or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. The term remuneration has been interpreted broadly to include anything of value. The federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers and formulary managers on the other. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution. The exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances. In addition, a person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it in order to have committed a violation. Rather, if “one purpose” of the remuneration is to induce referrals, the federal Anti-Kickback Statute is violated.

The federal civil monetary penalties statute imposes penalties against any person or entity who, among other things, is determined to have knowingly presented or caused to be presented a false or fraudulent claim to, among others, a federal healthcare program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.

VOR US Equity

VOR · 10-K · period ended 2022-12-31

Item 1. Business.

VOR US Equity☆

VOR · 10-K · period ended 2022-12-31

Item 1. Business.

VOR US Equity